Sympathetic neural control of blood pressure across the premenopausal lifespan

The technique of microneurography has advanced our understanding of the sympathetic nervous system’s role in the neurovascular control of blood pressure in humans, yet critical knowledge gaps remain, particularly across the premenopausal female lifespan. Historically, premenopausal females have been considered relatively protected from cardiovascular diseases, leading to a disproportionate focus on postmenopausal populations in cardiovascular research. However, emerging evidence contradicts this assumption: premenopausal females with hypertension exhibit 15–20% higher mortality rates than age-matched males, and myocardial infarction deaths are rising fastest among females under the age of 45. This review addresses a major void in the literature by examining sympathetic regulation of blood pressure in premenopausal females and how it is modulated across unique reproductive health states, including menstrual cycling, hormonal contraceptive use, pregnancy, polycystic ovary syndrome, uterine fibroids, and endometriosis. Muscle sympathetic nerve activity fluctuates with some but not all hormonal changes, depending on the population and the conditions under which they are studied. Moreover, corresponding effects on blood pressure vary widely, suggesting a high degree of variability in how sympathetic outflow is transduced into blood pressure in females. Overall, our review highlights the need for longitudinal and mechanistic studies focused on hormonal transitions and specific premenopausal health states to better understand, and eventually mitigate, female-specific cardiovascular risk.

Cardiovascular diseases (CVD) are the leading cause of death in females globally (1). Hypertension, a major cardiovascular risk factor, increases with age in a sex-dependent manner (2, 3). Although cross-sectional studies consistently show a higher prevalence of hypertension in postmenopausal compared with premenopausal females, longitudinal data directly examining blood pressure changes through the reproductive (i.e., post-adolescent, premenopausal) lifespan are limited (4–7). As such, premenopausal females are generally thought to be protected from CVD, a protection that has been attributed mainly to the cardio-protective benefits of estrogen (4, 8). However, CVD risk is not exclusive to postmenopausal females. For example, mortality rates from cardiovascular diseases are 15–20% higher in females (aged 35–45 yr) with hypertension compared with age- and blood pressure-matched males (9). Thus, despite common misconceptions regarding the cardio-protection afforded to females in their premenopausal years, it is critical to acknowledge that premenopausal females are not exempt from CVDs. Unfortunately, the focus on mitigating CVD risk in postmenopausal females has resulted in a dearth of data across the premenopausal and early perimenopausal period, which may be a critical window for therapeutic intervention and prevention (10, 11). Ultimately, understanding the mechanisms contributing to CVD risk in females can enable early disease prevention through the identification of female-specific mechanisms of cardiovascular health. The sympathetic nervous system is a key determinant of blood pressure homeostasis such that elevated sympathetic outflow is associated with both hypertension and elevated CVD risk (12, 13). Nonetheless, the relationship between resting muscle sympathetic nerve activity (MSNA) and blood pressure appears modest, with studies indicating a weak association among healthy adults (14). This suggests that although sympathetic tone contributes to long-term regulation, it is not the main determinant of blood pressure “set-point.” Moreover, MSNA also varies among individuals, influenced by factors such as age, sex, and lifestyle (15). Therefore, small changes in MSNA under different conditions may still fall within normal ranges, emphasizing the importance of contextualizing small changes within normal physiological ranges. Nevertheless, it has been established reasonably well that resting MSNA increases steadily with age in males (16, 17). In contrast, the pattern of age-related changes in sympathetic activity in females was previously considered less well-defined; however, relatively recent studies have demonstrated that females may exhibit a more rapid increase in MSNA with age (>30 yr) compared with males (16, 18). As such, it is reasonable to propose that the sympathetic nervous system is an important contributor to the progression of CVD risk across the female lifespan, wherein studies have demonstrated that sympathetic outflow is significantly higher in postmenopausal compared with premenopausal females (17, 19–21), findings which have been summarized recently in an excellent review by Fu (22). Efferent sympathetic nervous system activity directed toward the skeletal muscle vasculature can be measured directly using the technique of microneurography and quantified as MSNA (23). An increase in MSNA promotes neurotransmitter release, primarily norepinephrine, from sympathetic nerve terminals (24, 25). In the classic cascade of neurovascular transduction, norepinephrine binds to postsynaptic α-adrenergic receptors on the vascular smooth muscle to promote vasoconstriction, an increase in total peripheral resistance, and ultimately an increase in blood pressure (26–31). Although norepinephrine primarily promotes vasoconstriction through postsynaptic α1- and α2-adrenergic receptors, it also binds presynaptic α2-adrenergic receptors to inhibit further norepinephrine release and postsynaptic β2-adrenergic receptors to mediate vasodilation, thereby attenuating the overall vasoconstrictor response (13, 32). It has long been held that both MSNA and blood pressure remain low across the premenopausal period before increasing abruptly following menopause. However, much of the evidence supporting this position has emerged from cross-sectional comparisons between young premenopausal (typically 20–30 yr old) females and older (>52 yr old) postmenopausal females (17, 23, 33, 34). Although blood pressure has been studied more broadly across the lifespan, there are far fewer studies that have simultaneously assessed MSNA and blood pressure across the premenopausal years (16, 18). These studies have contradicted the concept of abrupt menopause-induced changes in MSNA and blood pressure, indicating that not only do MSNA and blood pressure increase in females prior to menopause, but also that the trajectory of blood pressure across the premenopausal lifespan does not parallel the trajectory of MSNA across that same period (16, 18). Together, these data can be interpreted in multiple ways. It is possible that the transduction of MSNA to blood pressure is not uniform across the premenopausal lifespan. However, it is also likely that these datasets have been influenced by the inclusion of female participants with undisclosed conditions that may affect MSNA and/or blood pressure (e.g., polycystic ovary syndrome and endometriosis), each of which affect ∼10% of females of reproductive age (35–37), emphasizing the need for rigorous female-centric cardiovascular studies that account for the presence of these unique reproductive health conditions. Review Scope and Contributions Interactions between MSNA and blood pressure provide important insight into the mechanisms that predispose females to CVD prior to menopause but remain understudied and thus incompletely understood (20, 23). Herein, we have summarized what is known about changes in the sympathetic control of blood pressure in females across the reproductive lifespan, defined as the period following adolescence prior to the onset of menopause. Given the known interplay between gonadal hormones and the sympathetic control of blood pressure (34), we pay particular attention to female-specific conditions associated with changes to the gonadal hormone milieu, including the menstrual cycle, oral contraceptive use, pregnancy, and females living with polycystic ovary syndrome, uterine fibroids, and endometriosis. In addition to outlining current knowledge, we indicate the areas of discrepancy, controversy, and/or incomplete information to highlight gaps in understanding that may impact female cardiovascular health and therapies for female-specific pathologies. Finally, this work aims to serve as a call to action for future investigations to focus on understanding sympathetic control of blood pressure in female-specific conditions to inform the development of novel, targeted, and personalized therapies for premenopausal females. EFFECT OF MENSTRUAL CYCLE ON SYMPATHETIC CONTROL OF BLOOD PRESSURE Premenopausal females experience repeated cyclical changes in hormones that typically span 24–32 days (38–40). These cyclical changes in hormones are divided into predictable and recurring phases defined by circulating hormone concentrations: early follicular (EF), late follicular (LF), mid-luteal (ML), and late luteal (LL) (41). When occurring in a consistent and predictable pattern, is often referred to as a “regular menstrual cycle.” In young premenopausal females with regular menstrual cycles, gonadotropic hormones such as follicle-stimulating hormone (FSH) and luteinizing hormone (LH) regulate circulating levels of 17β-estradiol (E2) and progesterone (P4) (41). Both E2 and P4 are lowest during the EF phase; E2 then peaks in the LF phase immediately prior to ovulation and following ovulation both E2 and P4 become elevated above EF levels during the ML phase. During the LL phase, which precedes menstruation, E2 and P4 levels begin to decline rapidly as the corpus luteum regresses, ultimately leading to the onset of menses (42). MSNA across the Menstrual Cycle A small body of literature has examined MSNA across menstrual cycle phases using the EF phase as a baseline for comparison. One study found no difference in MSNA between the LF and EF phases (43). Several studies have reported greater resting MSNA during the ML phase compared with EF (44–46), although others observed no significant difference between ML and EF (47, 48). Importantly, in a retrospective multicenter study from females tested during both the EF and ML phases, Carter et al. (44) demonstrated that menstrual cycle-related increases in E2 were inversely correlated with changes in MSNA, and that the ratio of E2 to P4 predicted MSNA fluctuations, suggesting a combined hormonal influence of both E2 and P4 on sympathetic activity. This interpretation is supported by experimental evidence from Day et al. (49) who used a GnRH antagonist to pharmacologically suppress circulating E2 and P4, resulting in a significant reduction in MSNA. These findings reinforce a complex, hormone-dependent regulation of MSNA. In interpreting the aforementioned data, it is important to consider that many menstrual cycle-focused studies examining MSNA have relied on calendar-based estimates to determine cycle phase (50). This method predicts the timing of hormonal phases based on the number of days since menstruation began, rather than through direct measurement of hormone levels. Other studies have omitted circulating hormone measurements altogether (48). However, both approaches may fail to capture the inter- and intraindividual variability in the magnitude and timing of fluctuations in E2 and P4, potentially leading to misclassification of menstrual cycle phases and limiting the accuracy of phase-specific comparisons (51). From a study design perspective, it is also important to note that the EF phase is most used as the within-subject control phase, whereas some studies compare female to male participants as a between-group reference (52). This variability in control conditions may contribute to the inconsistent findings across the literature. Moreover, the lack of consistency across studies, particularly the limited data from the LF phase, underscores the need for more comprehensive, phase-confirmed investigations into the interplay between endogenous hormones, MSNA, and blood pressure regulation. Endogenous sex hormones, including E2 and P4, are hypothesized to influence sympathetic regulation of blood pressure (44). These effects may occur through both direct mechanisms, such as modulation of central autonomic control centers, and indirect pathways, including vascular actions that subsequently alter sympathetic tone through compensatory feedback (53). E2 consistently demonstrates sympatho-inhibitory effects, supported by both human and animal studies (54). In contrast, the role of P4 appears more context-dependent, whereas some evidence suggests a possible sympatho-excitatory effect (43, 46, 55), other findings suggest little to no consistent influence, underscoring the need for further mechanistic investigation. Although E2 and P4 are the most well-described circulating hormones fluctuating across the menstrual cycle, gonadotropins, such as the follicular stimulating hormone (FSH) and luteinizing hormone (LH), also exhibit substantial variability both between individuals (interindividually) and within the same individual over time (intraindividually) and may contribute to sympathetic regulation (40). FSH and LH, secreted by the anterior pituitary, regulate ovarian steroidogenesis and modulate downstream E2 and P4 levels (41). To our knowledge, no studies have specifically evaluated whether fluctuations in gonadotropins across the menstrual cycle are associated with changes in MSNA in healthy premenopausal females. However, changes in gonadotropins occur in concert with changes in E2 and P4 (38), and thus it is possible that gonadotropins may contribute to changes in resting MSNA across the menstrual cycle wherein MSNA is higher during the ML phase (low FSH, high LH) than in the EF phase (high FSH, low LH) (34, 38). This knowledge gap is significant given recent findings suggesting that elevated FSH and LH may be more predictive of age-related vascular endothelial dysfunction than E2 alone (56). Moreover, as females approach perimenopause, often beginning in the early 40s (8, 11), FSH becomes increasingly variable (40), raising questions about its potential influence on the sympathetic neurovascular control of blood pressure. MSNA Reactivity across the Menstrual Cycle In addition to resting measures, several studies have assessed sympathetic responsiveness to physiological stressors. For example, Jarvis et al. (48) found no difference in MSNA reactivity (quantified as relative increases in MSNA from baseline) during the cold pressor test (CPT) between EF and ML phases. Similarly, isometric handgrip exercise, circulatory occlusion, and mental stress did not elicit menstrual phase-related differences in MSNA (46, 48, 57). In contrast, two studies reported greater MSNA responses to orthostatic stress (e.g., head-up tilt, lower body negative pressure) during the ML versus EF phase, particularly at high baroreceptor unloading intensities (e.g., >−40 mmHg) (57, 58). Interestingly, both Usselman et al. (59) and Sayegh et al. (60) showed that MSNA responses to chemoreflex activation (hypoxic-hypercapnic apnea) were lower in the ML phase compared with the EF in young females. In a retrospective analysis of data, studies reported that the ML phase was associated with lower MSNA burst amplitude than EF during chemoreflex activation, potentially reflecting a suppression of neural recruitment during ML when E2 and P4 are elevated (61). Unfortunately, studies assessing MSNA reactivity across menstrual cycle phases have omitted the LF phase and suggest that any menstrual cycle phase dependency of MSNA reactivity is highly dependent on the nature of the stimulus, arguing against a central potentiation of MSNA reactivity, and suggesting instead that any differences between phases arises through afferent pathways. Baroreflex Implications of the Menstrual Cycle Measures of sympathetic baroreflex gain and spontaneous baroreflex sensitivity appear generally stable across phases (47, 62), although some variation emerges depending on the assessment method. For example, although spontaneous and Valsalva-based measures reveal no differences between ML and EF phases (47, 62), the modified Oxford method has revealed greater baroreflex sensitivity during ML compared with EF (46). Although E2 appears to exert sympatho-inhibitory effects through both direct and indirect mechanisms, the role of P4 remains unclear. Resting MSNA tends to be higher during ML than EF, but several studies report no difference between phases. Responses to physiological stressors also vary by phase, with orthostatic and chemoreflex challenges revealing opposing phase-dependent modulation of MSNA. The limited and variable data on the LF phase and gonadotropins, as well as the underrepresentation of vascular measures, underscore the need for comprehensive, mechanistic research to unravel the neurovascular contributions to blood pressure regulation across the menstrual cycle. Although the literature evaluating MSNA across the menstrual cycle is growing, very few studies have directly assessed downstream transduction to vascular tone or blood pressure. Most investigations focus on neural output (i.e., MSNA) without concurrent measurements of vascular conductance or resistance, leaving a major gap in understanding how sympathetic nerve activity translates into functional hemodynamic outcomes across the menstrual cycle (46, 57, 59). The lack of simultaneous recordings of MSNA and vascular responses limits interpretation of whether phase-related changes in MSNA meaningfully affect end-organ responses such as vasoconstriction or augmented blood pressure levels (63). Overall, the relationship between menstrual cycle phase and sympathetic neural control of blood pressure in premenopausal females is complex and the literature is filled with inconsistent and/or context-dependent findings. Implications of Menstrual Cycle for Vascular and Blood Pressure Outcomes To date, only a few studies have included basic hemodynamic measures such as blood pressure, and comprehensive assessments of sympathetic neurovascular transduction across the menstrual cycle remain absent (46, 59). This omission is critical, as increased MSNA does not always result in increased vascular resistance or blood pressure due to compensatory mechanisms, receptor sensitivity, and local vascular factors, all of which may be influenced by fluctuating sex hormones (17, 64). For example, although most studies report lower resting MSNA in younger females compared with age-matched males (20), sympathetic vascular transduction at rest is generally not different between young healthy females and male, with similar blood pressure and vascular responses per MSNA (50, 52, 65). Importantly, reported findings can vary depending on the analytical approach used. Traditional regression-based methods and signal-averaging techniques quantify sympathetic transduction differently, and methodological differences may partially explain discrepant findings across studies (24, 65). Thus, apparent sex differences in sympathetic transduction should be interpreted cautiously and in the context of the analytical framework and experimental conditions used. Likewise, menstrual cycle phase has been associated with changes in blood pressure, though this body of research is limited, and the findings remain inconsistent (66). Several studies have indicated a modest increase in blood pressure during the ML phase compared with the EF phase (19, 42, 45, 49, 66, 67), whereas one study reported slightly elevated blood pressure during the EF phase compared with the LF phase (66), and others have reported no consistent changes in blood pressure across phases (65, 68). These insights emphasize the need for future studies to include simultaneous neural and vascular measures across hormone-defined menstrual phases to clarify whether MSNA changes translate into meaningful physiological outcomes, including blood pressure. Table 1 summarizes sympathetic and vascular findings across menstrual phases. | Phase/Condition | Ovarian/Endocrine Pattern | Resting MSNA | MSNA Reactivity (Stressors) | Baroreflex Sensitivity | Vascular Measures (Endothelial/Reactivity) | |---|---|---|---|---|---| | MENSTRUAL CYCLE | ||||| | LF (vs. early follicular) | ↑ E2, ↓ P4, FSH stable, LH rising | Insufficient data; limited direct comparisons | Not well studied | Not well studied | Inconsistent; possible mild vasodilatory effect due to E2 | | ↓ML (vs. early follicular) | ↑ E2, ↑ P4, ↓ FSH, ↑ LH | ↑ (variable) | ↓ chemoreflex response; ↑ orthostatic response | May be increased (Oxford method), variable, protocol dependent | No change | | LL (vs. early follicular) | Declining E2 & P4 | Not well studied | Not well studied | Not well studied | Not well studied | | HORMONE USE | ||||| | Oral contraceptive use (Variable changes across OCP phases, dependent on progestin type) | Ethinyl estradiol ± progestins | Similar to naturally cycling women (placebo phase) | Variable; depends on progestin | Variable | Modest changes in vascular function; formulation-specific | | PREGNANCY | ||||| | Healthy pregnancy (vs. nonpregnant females) | ↑ E2, ↑ P4 | ↑ Resting MSNA with gestation | Altered (context-dependent) | Altered BRS; unclear in normal pregnancy, better documented in complicated pregnancy | ↓ Transduction (vasodilation despite ↑ MSNA) | | Preeclampsia (vs. healthy pregnancies) | ↓ E2, ↓ P4; ↑ sFlt-1, ↑ sEng, ↓ PlGF | ↑ Sympathetic activity | Exaggerated pressor response | Impaired BRS | Endothelial dysfunction, antiangiogenic profile | | REPRODUCTIVE CONDITIONS | ||||| | PCOS (vs. control females without PCOS) | ↑ Androgens, ↑ Testosterone; insulin resistance | ↑ Resting MSNA | Enhanced reactivity | Altered (heterogeneous) | Endothelial dysfunction, ↑ CV risk | | Endometriosis (vs. control females without endometriosis) | ↑ E2; chronic inflammation | Autonomic function unclear, Limited direct data; possible autonomic imbalance | No data | No data | Endothelial dysfunction and ↑ CVD risk | | Uterine fibroids (vs. control females without UFs) | Local ↑ E2 exposure | ↑MSNA =↓CO ↑MSNA = ↑TPR | No data | No data | Cardiac output and stroke volume higher in UF, but not significant | BRS, baroreflex sensitivity; CO, cardiac output; CV, cardiovascular; E2, estradiol; FSH, follicle-stimulating hormone; LF, late follicular; LH, luteinizing hormone; LL, late luteal; ML, mid-luteal; MSNA, muscle sympathetic nerve activity; OCP, oral contraceptive; P4, progesterone; PCOS, polycystic ovary syndrome; PlGF, placental growth factor; sEng, soluble endoglin; sFlt-1, soluble fms-like tyrosine kinase-1; TPR, total peripheral resistance; UF, uterine fibroid. ↑, increase, ↓, decrease, ±, depending on. EFFECT OF ORAL HORMONAL CONTRACEPTIVE USE ON SYMPATHETIC CONTROL OF BLOOD PRESSURE Oral contraceptive pills (OCPs) significantly change the circulating hormone milieu, thereby altering the menstrual cycle and suppressing ovulation (69), further complicating our understanding of sympathetic control of blood pressure in females. Although hormonal contraceptives also include transdermal patches and intrauterine devices, most available data on whether hormonal contraceptives impact sympathetic control of blood pressure emphasize OCPs, as will this review. In the United States, ∼14% of premenopausal females (age 15–49 yr) were taking OCPs between the years of 2017–2019 (70). OCP use lowers endogenous female ovarian hormones throughout the menstrual cycle and is commonly prescribed to premenopausal females for a variety of indications above and beyond contraception, including but not limited to menstrual disorders and hormonal acne (71). A recent analysis of epidemiological evidence supports an association between past and current OCP use and hypertension (risk 1.2–1.9 times higher vs. non-OCP users) (72), although mechanisms are unclear. Conceivably, sympathetic neural mechanisms may play an important role in the association between hormonal contraceptives and blood pressure elevations, but evidence probing this link is limited and ambiguous. Anecdotally, we note that in recent years a shift in female recruitment has occurred: while OCP users were previously more readily recruited, current cohorts of females include a larger proportion of participants using intrauterine devices (IUDs) and with natural menstrual cycles. This shift poses a barrier to OCP-focused research, an issue that is further complicated by the variability in OCP generation (classification based on types of progestins in the pill, including 1st, 2nd, 3rd, and 4th generations) and variation of hormone doses across the pill pack (monophasic, biphasic, triphasic). As such, generalizations that span all OCPs should be interpreted with caution, and the data presented below are predominantly discussed on a study-by-study basis. MSNA and Implications for Blood Pressure: OCP Users versus Non-Users In comparing OCP users to females with regular, natural menstrual cycles, multiple sources have suggested that OCP use does not alter resting levels of MSNA in premenopausal females (45, 58, 73, 74), but these same reports differ in whether blood pressure is altered by OCP. Indeed, while one study reported higher systolic, diastolic, and mean arterial pressure in females taking OCP compared with females with natural menstrual cycles (45), others have reported no effect of OCP on the gold-standard measure of 24-h ambulatory blood pressure (73) or on seated office blood pressure (58, 73, 74). The discrepancy between these cross-sectional findings and the 1990–2010s epidemiological studies in the United States, Europe, and Asia may be explained by inconsistencies in OCP generation (e.g., dose and progestin types), phase of blood pressure measurement [active pill (i.e., hormone pill containing progestin only or combined estrogen and progestin) vs. placebo pill (i.e., inactive pill without hormones)], and the magnitude of blood pressure effects (72, 75, 76). For example, the observable increase in blood pressure with OCP use may be <1 mmHg in epidemiological studies of females free from overt CVD and risk factors (i.e., history of hypertension, diabetes, or recent pregnancy) (72). However, this rise in blood pressure in OCP users increases to 2–6 mmHg when CVD risk factors are not accounted for (72, 75, 76). In addition, prospective data support greater elevations in blood pressure with greater duration of use (≥2 yr) and increasing dose of progestin (progestin range <1.0–3.0 mg) (75). Of note, others report no association between progestin-only OCP and high blood pressure (76). More information on the current evidence and recommendations for OCP use is reviewed in detail elsewhere (72). The effect of OCP use on the relationship between MSNA and blood pressure is unclear. Harvey et al. (45) found no association between resting MSNA and mean arterial pressure in females taking OCP (with no difference detected between mono, bi, and triphasic types), despite a positive association between resting MSNA and mean arterial pressure in naturally cycling females. However, it should be noted that this association between resting MSNA and blood pressure was not previously observed in young females (77). MSNA across Phases of OCP Use Evidence has also indicated that resting MSNA is elevated during the active pill phase of OCP use compared with the placebo pill phase (58, 73, 78). Conversely, earlier work reported no effect of pill phase on MSNA in females taking OCP, though these studies did not include females with regular, natural menstrual cycles for comparison (79) and were retrospective (80). Taken together, the literature supports the hypothesis that elevated hormone levels may contribute to heightened sympathetic activity (44, 46). It is important to acknowledge that sex hormones, including synthetic hormones within OCP, can cross the blood-brain barrier with the potential to modulate sympathetic outflow (81). Importantly, the effects of E2 on MSNA differ depending on the brain area exposed to the hormone in preclinical models (81). Furthermore, exogenous (ethinyl estradiol, EE) may not confer the same vascular effects as endogenous estrogen (i.e., E2) (82). Regardless of whether hormones are exogenous or endogenous, there are two potential mechanisms for the rise in MSNA during the high hormone phase (i.e., active pill for OCP and ML phase for naturally cycling females) that have been proposed: 1) higher levels of circulating estrogens alter central mediation of sympathetic outflow (81); or 2) vascular responsiveness to estrogen (i.e., vasodilation) (83) elicits a compensatory baroreflex-mediated rise in MSNA to maintain perfusion pressure. MSNA across Phases of OCP Use Impacts on Blood Pressure Several studies have examined whether the phase of the OCP use (active hormone pills vs. placebo pills) influences resting MSNA, and importantly, whether any observed change in sympathetic activity is translated into blood pressure. Across studies of females using combined OCPs, while MSNA is modestly elevated during the active pill phase compared with the placebo pill phase, resting blood pressure remains unchanged. Carter et al. (80) demonstrated that resting mean arterial pressure (MAP) was identical between phases (85 vs. 84 mmHg). Similarly, Middlekauff et al. (73) reported no differences in 24-h ambulatory systolic blood pressure, diastolic blood pressure, or MAP between active and placebo pill phases. Usselman et al. (78) also observed comparable baseline blood pressure across phases despite higher MSNA during the high-hormone phase. The only exception is Minson et al. (79), who found higher MAP during the placebo pill phase. Collectively, these findings suggest that phase-related increases in MSNA during OCP use do not translate into meaningful elevations in resting blood pressure within the same individuals. This dissociation may reflect effective buffering by vascular and baroreflex regulatory mechanisms. Although no consistent and statistically significant differences in blood pressure have been observed between the active and placebo pill phases, we note that the studies were not specifically powered to detect very small changes in blood pressure (e.g., 1–2 mmHg). Baroreflex Implications of OCP Use OCP use may impact arterial baroreflex modulation of blood pressure in females. Severe [−80 mmHg (58)], but not mild-moderate [−5 to −40 mmHg (80)] lower body negative pressure elicited greater increases in MSNA during the high hormone phase (active pill) versus low hormone phase (placebo pill) in females taking OCP, majority monophasic, combination pills (20–35μg EE with varying types of progestin during the high hormone phase) (58, 80). Notably, the rise in MSNA during severe lower body negative pressure was not different in females taking majority monophasic, combination OCP compared with naturally cycling females during neither the high (active pill, ML phase) nor low hormone phase (placebo pill, EF phase) (58). Using the modified Oxford approach, early work reported lower sympathetic as well as cardiovagal baroreflex sensitivity during the active pill versus placebo pill phase in females taking monophasic, combination OCP (30–35 μg EE and low-dose progestin) (79). Later, another group performed similar experiments comparing females taking the majority triphasic, combination OCP with naturally cycling females but did not find differences in sympathetic or cardiovagal baroreflex sensitivity between groups or hormonal phases (73). In addition, Middlekauff et al. (73) included a non-baroreflex mediated sympathetic stimulus CPT and similarly reported no effect of OCP or hormonal phase on the MSNA and blood pressure responses. Taken together, controlled (i.e., with a naturally cycling female comparison group) studies demonstrate limited or no role of OCP on arterial baroreflex modulation of sympathetic control of blood pressure, although this may depend upon OCP type (e.g., monophasic vs. triphasic, combination vs. progestin only). MSNA Reactivity across Phases of OCP Use Sympathetic neural and blood pressure responses to chemoreflex activation have yet to be directly compared between females taking OCP and naturally cycling females. However, Usselman et al. (78) demonstrated a lower rise in MSNA during chemoreflex activation (via apnea) during the active than the placebo phase in females taking different types and generations of OCP. Interestingly, lower MSNA responses to chemoreflex stress during the active phase occurred despite greater resting MSNA compared with the placebo phase (78). MSNA was not different between hormonal phases at peak chemoreflex activation, suggesting that hormonal modulation may influence the gain or pattern of sympathetic responsiveness rather than the maximal achievable response. Vascular Implications of OCP-Induced Changes in MSNA Sympathetic vascular transduction, the ability of MSNA bursts to elicit rapid peripheral vasoconstriction and blood pressure changes, has been assessed using several methodological approaches in humans (65). In their most recent work, D’Souza et al. (74) examined whether OCP use alters sympathetic vascular transduction at rest in young females. In this study, transduction was defined as the mean change in leg vascular conductance per MSNA burst, calculated from beat-to-beat duplex Doppler ultrasound measures of leg blood flow and mean arterial pressure (Finometer). Despite higher baseline MSNA in OCP users, neither the absolute (Δ) nor relative (%Δ) decrease in leg vascular conductance following a burst of MSNA differed between OCP users and naturally cycling females tested during the mid-luteal phase. The authors interpreted this as an attenuated vascular response because higher MSNA did not translate into proportionally greater vasoconstriction (65). However, previous studies from the same group have used different analytical definitions of transduction. One approach quantified transduction using burst-triggered averaging, examining the immediate beat-to-beat vasoconstriction that follows each MSNA burst (84) and indicated that females using OCPs demonstrated attenuated sympathetic transduction into leg vascular conductance (84). Another approach evaluated transduction using time-averaged limb vascular conductance normalized to MSNA burst frequency across a defined period, reflecting overall vasoconstrictor responsiveness during a physiological stressor (i.e., isometric handgrip exercise) (74), and indicated that sympathetic vascular transduction of MSNA burst amplitude and total action potential clusters were greater in both males and in females using OCPs compared with menstruating females not using OCPs (74). These methodological differences—burst-triggered versus time-averaged analyses, local versus total vascular conductance and resting versus exercise conditions—likely contribute to divergent findings across studies. Notably, during peak handgrip exercise, D’Souza et al. (74) also observed recruitment of previously dormant sympathetic axons in OCP users, demonstrated by the appearance of higher-threshold action-potential clusters within MSNA bursts. Because recruitment of additional axons is associated with larger norepinephrine and co-transmitter release, this pattern suggests a shift from increasing burst amplitude within active fiber toward recruitment of new fibers, which may enhance vasoconstrictor drive during exercise (85). Summary and Limitations of OCP Literature Taken together, OCP use lowers endogenous ovarian hormones and appears to modulate sympathetic control of blood pressure in females, with alterations to autonomic reflex function. Some (58, 78, 79), but not all (73, 80), studies suggest hormonal phase (i.e., placebo vs. active pill) influences sympathetic responses to baroreflex loading/unloading and chemoreflex activation in OCP users. Specifically, severe, but not mild-moderate, baroreflex unloading reduces blood pressure in females taking OCP but not naturally cycling females (58, 80). In addition, sympathetic vascular transduction is elevated during handgrip exercise in females taking OCP (74). These suppositions are subject to several limitations, including a narrow participant age range and incomplete data concerning OCP progestin levels, all of which may influence blood pressure regulation and/or sympathetic activity. In particular, there is a paucity of robust data in females aged 30–50 yr taking hormonal contraceptives, likely due, in part, to the decline in OCP usage among this age group (70). The lack of data in this age group of females is concerning as MSNA increases after age 30 at an accelerated rate in females compared with males (16); however, it must be noted these conclusions come from a female cohort including both OCP and non-OCP users without differentiation (16). It is also worth noting that OCPs are known to increase plasma volume, angiotensinogen, angiotensin II, and aldosterone levels, all of which increase blood pressure (84, 85). Furthermore, central angiotensin II increases sympathetic outflow (86), but how these chronic changes with prolonged OCP use interact and modulate neural control of blood pressure remains uncertain. Future research that addresses these gaps, particularly in younger, premenopausal females and with more precise control over OCP generation and type, is warranted for fully elucidating the cardiovascular implications of OCP use and its effect on sympathetic neural control. EFFECT OF PREGNANCY ON SYMPATHETIC NEURAL CONTROL OF BLOOD PRESSURE Considerable advances in research over the past 20 years have illuminated how pregnancy fundamentally alters autonomic cardiovascular regulation, including implications for cardiac function, vascular tone, renal physiology, and neuroendocrine signaling (87, 88). Pregnancy is a critical period wherein several cardiovascular changes occur to support the developing fetus. Over the course of a healthy 40-wk pregnancy, maternal blood volume and cardiac output increase by 50% and 30%, respectively (89), while overall cardiovascular risk also rise during this period (88, 89). Despite elevated cardiac output, mean arterial pressure decreases during healthy pregnancy due to lower total peripheral resistance (TPR) (90, 91). Moreover, increased blood volume and cardiac output enhance atrial stretch, triggering atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) release, which promote vasodilation and reduce blood volume, a mechanism that helps counteract hypertension and maintain blood pressure stability. Given the central role of the sympathetic nervous system in maintaining cardiovascular homeostasis, it is important to consider sympathetic regulation during pregnancy. MSNA during Healthy Pregnancies In uncomplicated pregnancies, MSNA begins to increase as early as the first trimester and continues to rise or remain elevated during the second and third trimesters, ultimately returning to baseline levels within 6 wk after delivery (48, 92–95). Among these, two longitudinal studies are particularly notable for tracking MSNA in the same individuals across gestation: one by Reyes et al. (95) and another by Hissen et al. (96). These within-subject designs provide compelling evidence for a consistent rise in sympathetic activity during pregnancy, reinforcing the idea that MSNA adaptation is a fundamental part of female cardiovascular physiology (91, 95). Resting total MSNA, burst frequency, and burst incidence are significantly higher in late pregnancy, typically defined as the third trimester (weeks 28–40), compared with both the nonpregnant state and early pregnancy (weeks 1–12) (92, 97). Vascular Implications of Pregnancy-Induced Changes in MSNA Despite elevations in MSNA with pregnancy, pregnant females exhibit lower transduction of the sympathetic signal into vascular outcomes, as evidenced by a reduced association between forearm vascular resistance and MSNA during head-up tilt compared with nonpregnant controls (48). Reduced transduction has been further indicated by lower TPR in healthy pregnant females relative to nonpregnant females (50, 95), which may reflect an adaptive blunting of vascular responsiveness, specifically, a diminished vasoconstrictive response through reduced α-adrenergic receptor sensitivity, such that for a given amount of norepinephrine released, there is less α-adrenergic receptor mediated vasoconstriction during pregnancy (98, 99). This adaptation may serve to protect against excessive vascular resistance in response to substantial volume expansion that occurs during pregnancy (98, 100). Both at rest and during the cold pressor test, the association between MSNA and TPR and/or blood pressure is weaker in pregnant compared with nonpregnant females, further supporting diminished neurovascular transduction during pregnancy (95, 101). Together, these findings indicate that pregnancy is associated with altered sympathetic control of vascular tone, likely as a physiological adaptation to prevent exaggerated pressor responses during a period of increased blood volume and cardiac output (102). Changes in Blood Pressure in Healthy Pregnancies In a healthy pregnancy, MAP decreases by mid-gestation despite an increase in cardiac output, due to a marked reduction in peripheral vascular resistance (103). During the first trimester, diastolic blood pressure declines, with Jarvis et al. (103) reporting a trend toward lower supine diastolic blood pressure early in pregnancy. This early reduction progresses to a mid-gestation nadir, after which blood pressure gradually rises, although it remains within a normal range (90, 104). In addition, Usselman et al. (50) observed elevated sympathetic outflow in pregnant females in the third trimester alongside reduced blood pressure compared with nonpregnant females. Collectively, these findings demonstrate that normotensive pregnancies are characterized by normal or slightly reduced blood pressure throughout gestation, even in the presence of heightened sympathetic activity. Baroreflex Implications of Healthy Pregnancies Studies demonstrate that pregnancy blunts the vascular effects of sympathetic outflow, indicative of altered baroreflex/vasomotor control. A longitudinal assessment study demonstrated that MSNA rises steadily across gestation (95), but neurovascular transduction decreases. That is, each sympathetic burst produces a smaller increase in vascular resistance or blood pressure during pregnancy. In addition, another study found that early pregnancy is characterized by higher MSNA yet lower total peripheral resistance and significantly blunted sympathetic vascular transduction (i.e., reduced α-adrenergic vasoconstrictive response) compared with nonpregnant females (103). These findings suggest a pregnancy-specific adaptation: although sympathetic activity is elevated, baroreflex-mediated vascular tone is reduced, likely due to reduced adrenergic responsiveness and enhanced vasodilatory influences that prevent excessive increases in blood pressure during the large volume expansion of pregnancy. MSNA in Preeclampsia Preeclampsia (PE), a pregnancy-specific condition marked by persistent de novo hypertension after 20 wk’ gestation, has been associated with elevated MSNA, although more recent evidence has drawn that into question. For instance, the earliest microneurography study in females with PE reported markedly elevated muscle sympathetic nerve activity (MSNA) in females with PE compared with normotensive pregnant controls, with levels returning to baseline postpartum (105). These findings, supported by subsequent investigations (106–108), led to the prevailing view that sympathetic overactivity is a hallmark of PE. However, a more recent study by Reyes et al. (109) indicated that MSNA is not elevated in females with PE relative to normotensive pregnant controls. However, a 2025 systematic review (101) re-examined all PE data collectively and concluded that MSNA is not uniformly elevated in PE, emphasizing methodological limitations such as small sample sizes, cross-sectional designs, and differences in disease severity or gestational timing (91, 110, 111). Therefore, it is important to clarify that although some studies are based on pregnant females actively experiencing PE (105–109), others have focused on females with related or comorbid conditions (91, 110, 111) or on long-term cardiovascular function in females with a history of PE (112, 113). Vascular Implications of Changes in MSNA in PE Beyond resting MSNA, the concept of neurovascular transduction provides additional mechanistic insight into the neurovascular regulation of blood pressure during pregnancy. Vascular sensitivity to sympathetic stimulation is typically blunted in healthy pregnancy (50, 107), potentially mitigating hypertensive responses despite pregnancy-related elevations in MSNA. This blunting in healthy pregnancy is thought to arise from enhanced vasodilator signaling (e.g., nitric oxide, prostacyclin) and reduced α1-adrenergic receptor responsiveness (114, 115). In contrast, the endothelial dysfunction and increased vascular stiffness characteristic of PE likely impair this pregnancy-related buffering capacity, potentially enhancing neurovascular transduction and amplifying the pressor effects of sympathetic drive. Direct evidence for altered sympathetic vascular transduction in PE remains limited; however, it has been proposed that altered transduction is a plausible mechanism linking autonomic dysregulation to the exaggerated vasoconstriction and hypertension observed in the disorder (102, 116). Baroreflex Implications of PE Baroreflex impairment is a well-documented feature of PE and has been associated with elevated MSNA (104, 117). Although a healthy pregnancy involves a modest reduction in baroreflex sensitivity, Fu and Levine (104) showed that females with PE exhibit a marked blunting of baroreflex function, accompanied by heightened sympathetic activity. This suggests a degree of autonomic dysregulation that exceeds normal gestational adaptations. Together, these findings indicate that both resting sympathetic nerve activity and baroreflex control mechanisms are disrupted in PE, though the underlying causes remain unclear and may involve complex hormonal, vascular, and neural interactions unique to the disorder. Notably, the autonomic disturbances in PE may persist beyond pregnancy: sympathetic overactivity and elevated blood pressure have been observed postpartum, potentially contributing to increased long-term cardiovascular risk (116). Thus, tracking the trajectory of MSNA and baroreflex function in both the acute and recovery phases of PE is essential for identifying females at heightened risk for future cardiovascular disease. MSNA in Gestational Hypertension and Gestational Diabetes Sympathetic overactivity is also observed in gestational hypertension (GH) (92, 101), a condition often accompanied by comorbidities like obesity and gestational diabetes mellitus (GDM). These conditions are independently associated with autonomic dysfunction, elevated resting MSNA, and impaired vascular regulation (91–93). In the context of GDM, increased resting MSNA, greater total action potential frequency at rest but reduced ability to recruit latent neurons, exaggerated neurovascular transduction, and heightened responses to stressors such as the CPT have been reported (118). Mechanistically, action potential frequency is directly related to systolic and diastolic blood pressure during pregnancy, highlighting altered sympathetic control of blood pressure in GH compared with healthy pregnancies (94). Although much of this work is based on human clinical data, animal models provide additional insight into the pathophysiology of sympathetic regulation in pregnancy-related hypertensive disorders (119). However, the current section focuses on human studies to ensure clinical relevance. Vascular and Blood Pressure Implications of GH and GDM GH is defined as the de novo onset of hypertension after 20 wk of gestation and thus its pathophysiology is strongly associated with maternal vascular dysfunction (120, 121). Clinical studies in hypertensive disorders of pregnancy including GH consistently demonstrate impaired endothelial function measured by reduced brachial artery flow-mediated dilation (FMD), supporting the presence of macrovascular endothelial dysfunction (120, 122, 123). Moreover, prospective data further suggest that endothelial dysfunction can precede the clinical manifestation of hypertensive pregnancy complications, indicating that vascular impairment is an early characteristic rather than a consequence of elevated blood pressure (122). In addition, arterial stiffness indices such as pulse wave velocity (PWV) and wave reflection parameters are altered in females with hypertensive disorders of pregnancy compared with normotensive pregnancies (124). Similarly, females with GDM exhibit impaired endothelial function and altered arterial properties during pregnancy and postpartum, including reduced FMD and abnormalities in arterial compliance (125, 126). Importantly, large cohort studies show that GDM is associated with an increased risk of subsequent chronic hypertension (121) and recent meta-analyses confirm a significantly elevated long-term hypertension risk following GDM (127). Together, these data support that while GH is primarily a hypertensive vascular disorder, GDM carries both vascular dysfunction and blood pressure implications that extend beyond pregnancy. In sum, altered sympathetic regulation is central to both normal cardiovascular adaptation and the development of complications during pregnancy. Healthy pregnancy is characterized by a physiological paradox: despite marked increases in cardiac output and resting MSNA, total peripheral resistance remains relatively stable, resulting in maintained or even reduced blood pressure. This adaptation is thought to reflect attenuated neurovascular transduction, effectively uncoupling MSNA from vascular resistance, to accommodate the demands of the growing fetus without hypertensive consequences. In contrast, conditions such as PE and GH are associated with exaggerated MSNA and impaired baroreflex function, contributing to elevated vascular tone and clinical hypertension. Although several recent reviews have explored these mechanisms in complicated pregnancies (91, 106, 111, 128), they collectively highlight the role of exaggerated sympathetic activity, impaired baroreflex control, and disrupted vascular regulation in the pathogenesis of hypertensive disorders such as preeclampsia and gestational hypertension (102). SYMPATHETIC NEURAL CONTROL OF BLOOD PRESSURE IN FEMALES LIVING WITH POLYCYSTIC OVARY SYNDROME Polycystic ovary syndrome (PCOS) is a complex, multisystem disorder characterized by ovarian dysfunction, hyperandrogenism, and polycystic ovarian morphology. PCOS affects 4%–21% of reproductive-aged females, depending on diagnostic criteria and the population studied (129). Importantly, strong evidence associates PCOS with increased hypertension and overall cardiovascular risk (130–135). Despite the high prevalence of hyperandrogenism (>75%) in females with PCOS (136), the effects of elevated circulating androgens on the sympathetic control of blood pressure in females remain poorly understood. It has been suggested that heightened MSNA may play a modulatory role in the elevated risk for hypertension in females with PCOS (35, 137). Research focused on the association between PCOS, MSNA, and blood pressure is in its infancy, and we have summarized the current understanding in the following sections and highlighted areas for future investigation. MSNA in PCOS There is relatively consistent evidence that PCOS is associated with elevations in resting MSNA (35, 137–140). Studies report elevated resting MSNA burst frequency (138), burst incidence (139), or both (140) in female cohorts of predominantly hyperandrogenic PCOS compared with healthy controls. It is thus peculiar that these reports do not report increases in blood pressure in individuals with PCOS versus controls (138–140). In contrast, other studies lacking measures of MSNA demonstrate greater resting blood pressure in non-hypertensive females with PCOS compared with controls (141–143), compounding the controversy surrounding neural control of blood pressure in females with PCOS. Discrepancies between blood pressure findings in females with PCOS may be related to the mode of assessment (i.e., ambulatory pressures vs. office or research laboratory pressures); for example, non-hypertensive females with PCOS had higher ambulatory pressures compared with controls, but office blood pressures were not statistically different between groups (141). Be that as it may, a meta-analysis of population-based studies indicated the incidence of hypertension is 1.87-fold higher in reproductive-aged females with PCOS compared with controls (134); whether the increased incidence of hypertension is related to elevated MSNA remains unclear. Vascular Implications of PCOS Females with PCOS exhibit endothelial dysfunction, characterized by impaired endothelium-dependent vasodilation and reduced responses to insulin-mediated vasodilatation (144–146) which appears to be associated with both hyperandrogenism and insulin resistance independent of obesity (e.g., impaired flow-mediated dilation and blunted vasodilatory responses) and may underlie the susceptibility to macrovascular disease in this population. Mechanistic work suggests that androgen excess contributes directly to microvascular endothelial impairment, potentially via endothelin-mediated pathways, further linking hormonal dysregulation with vascular dysfunction in PCOS (147, 148). Functional vascular control is also altered in PCOS, wherein acute hyperemic responses to dynamic exercise are blunted in lean females with PCOS relative to matched controls, indicating compromised skeletal muscle blood flow regulation even in the absence of overt obesity, and suggesting early vascular dysregulation in otherwise healthy individuals (149). Furthermore, young females with PCOS demonstrate exaggerated blood pressure and vascular responses to sympathoexcitatory stressors such as the cold pressor test, with these responses correlating with bioavailable androgens, indicating enhanced sympathetic-vascular reactivity that may determine future hypertension and cardiovascular disease (144). These findings support a framework in which endothelial dysfunction, impaired vasodilatory capacity, and altered autonomic-vascular control contribute to the heightened cardiovascular risk observed in PCOS. Baroreflex Implications of PCOS To date, relatively few studies have directly assessed baroreflex function in females with PCOS. One clinical study reported that females with PCOS exhibited reduced spontaneous baroreflex sensitivity (BRS) compared with controls, and that this reduction may be influenced by increased adiposity, although the independent effect of PCOS per se remains unclear (150). Animal and human mechanistic data also suggest that androgen excess and elevated SNA activity may impair baroreflex gain and contribute to blood pressure dysregulation, but definitive physiological evidence in PCOS populations is currently limited (151). To the best of our knowledge, there have not been any published reports of comprehensive cardiovagal or sympathetic vascular baroreflex sensitivity assessments in females with PCOS beyond these early findings, leaving a gap in understanding how baroreflex control of heart rate and vascular resistance is modulated in this condition. Blood Pressure in PCOS To the best of our knowledge, there have yet to be studies reporting both MSNA and blood pressure in hypertensive females with PCOS, although hypertension is a common comorbidity of PCOS (133–135). It is thus important to probe the role of MSNA on blood pressure in hypertensive females with PCOS to improve our understanding of sympathetic neural control of blood pressure in PCOS. Fortunately, prior work has considered the impacts of obesity (151, 152) and insulin resistance (151, 153), which often accompany PCOS and exacerbate cardiovascular disease risk in these females (133). For example, female cohorts of predominantly hyperandrogenic PCOS were often compared with healthy control groups matched for body mass index (BMI) (138, 139) and/or insulin resistance (151). Indeed, in one study, BMI was significantly higher in the control group compared with females with PCOS, and yet MSNA was still elevated in the PCOS group (138). As such, it is unlikely the elevations in MSNA with PCOS are attributable solely to obesity (154) or insulin resistance (155). MSNA Reactivity in PCOS A recent study demonstrated that sympathetic activation from the CPT evoked greater blood pressure responses in young, normal weight females with PCOS compared with controls, although MSNA was not measured (144). Importantly, pressor responses to CPT were positively associated with androgen levels, implicating hyperandrogenism in exaggerated blood pressure responses to physiological stress in PCOS (144). In response to isometric handgrip exercise, females with PCOS exhibit greater increase in MSNA burst frequency and possibly blood pressure (P = 0.058 for mean arterial pressure) compared with BMI-matched controls (156). In contrast, the MSNA responses to baroreceptor unloading with lower body negative pressure were similar between females with hyperandrogenic PCOS and controls with obesity and associated insulin resistance (151). Unfortunately, the role of PCOS on sympathetic neural control of blood pressure responses to other forms of autonomic reflex activation, such as peripheral or central chemoreflex, has not been examined. Thus, there is a paucity of data on the MSNA-blood pressure responses to sympathetic stress in females with PCOS, warranting investigation to further our understanding of PCOS pathophysiology. Summary and Challenges in the Study of MSNA in PCOS Another difficulty surrounds the control for menstrual cycle phase in females with PCOS who present with irregular menstrual cycles, oligomenorrhea, or amenorrhea. The lack of menstrual-cycle phase-controlled studies in females with regular menstrual cycles and oligomenorrhea likely has implications in terms of the effects of hormone fluctuations on blood pressure and MSNA. This difficulty may be partially accounted for by measuring plasma sex hormones including estrogen and progesterone [indeed, one study demonstrated that circulating E2 was greater in androgen-excess PCOS compared with females without PCOS (151)]; however, past work has generally reported plasma testosterone and sex-hormone binding globulin but not E2 or progesterone (138–140, 157). Thus, studies should note the menstrual cycle phase and/or collect blood samples to report ovarian hormone concentrations (i.e., E2, P4) to best describe the phase at the time of testing. Moreover, studies examining the sympathetic control of blood pressure in females with PCOS frequently neglect to report (139, 140, 156) or exclude for OCP use (138, 151), which is a front-line treatment for PCOS (36, 158). As previously discussed, menstrual cycle phase and OCP use may impact blood pressure regulation in females and their implications in PCOS should be considered in future work. Finally, PCOS is a complex clinical syndrome with multiple phenotypic presentations (e.g., hyperandrogenic PCOS, non-hyperandrogenic PCOS, PCOS with eumenorrhea, hyperandrogenic oligomenorrhea) that may have a significant impact of neural control of the circulation; the differential effects of these phenotypes on MSNA, blood pressure, and cardiovascular disease risk are poorly understood and warrant investigation. SYMPATHETIC CONTROL OF BLOOD PRESSURE IN FEMALES LIVING WITH UTERINE FIBROIDS Uterine fibroids (UFs), or leiomyomas, are benign, E2 and P4-sensitive smooth muscle tumors of the uterus that affect an estimated 70%–80% of females during their reproductive years (159). Diagnosis is typically confirmed via pelvic ultrasound or MRI and is based on number, size, and location of the fibroids (intramural, subserosal, or submucosal) (159, 160). Although often described as a localized gynecologic issue, UFs are increasingly recognized for their systemic effects, including impacts on vascular health and blood pressure regulation. In addition to higher rates of hypertension, some studies report vascular dysfunction in females with UFs, including impaired flow-mediated dilation, though findings remain inconsistent (5, 159, 160). Population-based studies have consistently reported a higher prevalence of hypertension in females with UFs, even after adjusting for confounders such as age, race, and BMI (5, 161). These associations raise the possibility that UFs may be linked to autonomic dysregulation, particularly elevated MSNA, a known contributor to vascular dysfunction and hypertension. To the best of our knowledge, only one study has used microneurography to directly assess MSNA in females with UFs (162). In that study, Harvey et al. (162) found no difference in baseline MSNA between UF and non-UF groups studied during the early follicular phase. However, in UF participants only, MSNA burst incidence correlated positively with TPR and negatively with cardiac output, suggesting altered neurovascular transduction in this group (162). The study sample included reproductive-age females (mean age ∼33 yr), with BMI and fibroid size representative of common clinical cases. Hormonal cycling offers an additional lens for exploring UF-MSNA interactions. Fibroid growth is known to fluctuate across the menstrual cycle, increasing in volume during the ML phase when both E2 and P4 levels peak (163). This aligns with findings of elevated MSNA during the ML phase in healthy females (see MSNA across the Menstrual Cycle), raising the possibility that fibroid burden may modulate, or be modulated by, autonomic output. However, whether UFs simply track with hormonal changes that also influence MSNA, or independently contribute to sympathetic activation, remains unknown. Contributing factors such as chronic pelvic pain, psychological stress, and systemic inflammation, commonly reported in females with UFs, may also drive heightened sympathetic outflow (164, 165). Moreover, hormonal suppression, often used as a nonsurgical treatment for fibroids, may offer a unique opportunity to investigate causal relationships between gonadal hormones, fibroid burden, and sympathetic control of blood pressure (159). Given the known associations between UFs and both cardiovascular risk and autonomic contributors to hypertension, further research is warranted to determine whether UF-targeted treatments can modulate MSNA or improve vascular function. Clarifying these pathways could have important implications for cardiovascular risk screening and management in females with fibroids. SYMPATHETIC CONTROL OF BLOOD PRESSURE IN FEMALES LIVING WITH ENDOMETRIOSIS Endometriosis is a chronic, estrogen-dependent inflammatory condition affecting ∼10% of females during their reproductive years (166). Although classically associated with pelvic pain and infertility, growing evidence suggests that endometriosis may also be linked to increased cardiovascular risk, including hypertension and vascular dysfunction (167, 168). In particular, flow-mediated dilation has been shown to be impaired in females with endometriosis, pointing to endothelial dysfunction as a potential contributor to vascular risk (168, 169). However, direct evidence of altered sympathetic control in this population remains extremely limited. Although no studies to date have directly assessed MSNA in individuals with endometriosis, some indirect evidence points to autonomic imbalance. Several studies using heart rate variability have reported alterations consistent with reduced parasympathetic and potentially increased sympathetic modulation of heart rate in females with endometriosis (150–152). However, it is important to note that heart rate variability indices, particularly low frequency (LF) and high frequency (HF) ratio (LF/HF), are not solely influenced by cardiac sympathetic nerve activity and reflect mixed autonomic influences that are highly context-dependent (1, 2). These findings should therefore be interpreted as suggestive of autonomic imbalance rather than definitive evidence of sympathetic dominance. In addition, recent evidence from Williams and Alexander (170) suggests altered sympathetic reactivity to stress in females with endometriosis. In their study, in contrast with the authors’ hypothesis, females with endometriosis demonstrated attenuated blood pressure responses to the CPT and handgrip exercise compared with healthy controls. This blunted responsiveness may reflect impaired sympathetic reactivity to physiological stress, warranting further investigation into underlying mechanisms. Such blunted blood pressure reactivity aligns with the broader hypothesis that chronic pain and inflammation may sensitize central autonomic circuits, ultimately alter sympathetic outflow and contribute to cardiovascular dysregulation (146). Moreover, there is also preliminary evidence that altered estrogen receptor (ER) signaling may contribute to autonomic and vascular abnormalities in this population. Endometriotic lesions exhibit changes in ER expression, with increased ERβ and decreased ERα, which may modify local and systemic E2 responses (166, 171, 172). Although these findings have not been confirmed in vascular tissue, such shifts in receptor balance could theoretically alter vascular tone or baroreflex sensitivity. E2 acting via ERβ is typically associated with vasodilation and attenuation of MSNA through nitric oxide pathways (173), and studies have shown that E2 enhances β-adrenergic receptor responsiveness in vascular smooth muscle (174, 175). However, whether these pathways are preserved or disrupted in endometriosis remains unknown. Given the limited and largely indirect nature of current evidence, it remains unclear whether individuals with endometriosis experience meaningful alterations in MSNA, baroreflex function, or sympathetic vascular transduction. Addressing this gap will require studies that incorporate direct assessments of sympathetic nerve activity alongside measures of endothelial function and baroreflex control. Such investigations are critical for determining whether autonomic dysfunction contributes to the elevated cardiovascular risk observed in this population. Recent exploratory work has begun to establish this line of inquiry laying the groundwork for future studies that could clarify both the physiological mechanisms and potential therapeutic targets in endometriosis-related cardiovascular dysregulation (166, 169, 170, 176–179). SYNTHESIS OF MSNA FINDINGS AND CAVEATS A functional sympathetic nervous system is essential for the maintenance of homeostasis. As a result, MSNA varies widely among individuals, and elevated MSNA is not necessarily pathological. In healthy young females, for example, Keir et al. (16) documented a substantial degree of variability in MSNA while remaining normotensive (18). In addition, certain physiological states, such as across the menstrual cycle and pregnancy, are associated with predictable increases in MSNA that reflect normal adaptive mechanisms. By contrast, the extent to which MSNA is elevated in female-specific pathological conditions, such as endometriosis, PCOS, or UFs, remains incompletely established. This variability, combined with the lack of standardized thresholds for “high” versus “low” MSNA, complicates interpretation and underscores the need for further research, particularly to determine whether observed increases in MSNA in female-specific pathological conditions represent maladaptive sympathetic overactivity or normal physiological adaptation (see Table 1). Recent efforts to establish standardized thresholds for MSNA [e.g., by Keir et al. (16)] show promise in this area. However, substantial interindividual variability among even healthy individuals without pathological conditions has complicated these efforts and ultimately led Keir et al. (16) to suggest that any values between the 5th and 95th percentiles of a relatively large cohort may be considered “normal.” Thus, we assert that more work is needed—particularly large-scale efforts that combine data across many laboratories—before clinically meaningful thresholds/normative ranges can be established. GOING FORWARD: ADVANCING THE UNDERSTANDING OF AUTONOMIC REGULATION AND ITS IMPLICATIONS IN FEMALE-SPECIFIC POPULATIONS Despite substantial progress in the field of autonomic cardiovascular regulation, our understanding of sympathetic neural control of blood pressure in premenopausal females remains incomplete. This review highlights the dynamic and context-dependent role of female gonadal hormones in modulating MSNA across both physiological and pathophysiological states. Although hormonal fluctuations are frequently associated with changes in MSNA, corresponding alterations in blood pressure or vascular resistance are not consistently observed. These discrepancies suggest the presence of compensatory mechanisms, such as modified neurovascular transduction or baroreflex sensitivity, that buffer the hemodynamic consequences of elevated sympathetic outflow. Such inconsistencies, particularly the apparent dissociation between MSNA and downstream vascular effects, underscore a critical need for longitudinal, mechanistic studies that span the female reproductive lifespan. Investigating transitional phases such as the menstrual cycle, pregnancy, and perimenopause is especially relevant in populations at elevated cardiovascular risk. Moreover, conditions like PCOS, UFs, and endometriosis present unique hormonal and inflammatory environments that may differentially influence autonomic regulation. Moving forward, future research should prioritize study designs that: 1. Account for interindividual variability in hormone profiles and autonomic responses. 2. Include diverse populations with respect to race, ethnicity, and reproductive history. 3. Integrate multiple modalities, including direct sympathetic recordings, baroreflex assessments, and hormone quantification. 4. Emphasize a translational physiological approach that includes studying the vascular and blood pressure implications of MSNA. 5. Leverage the controlled conditions of animal models to manipulate key variables, including circulating hormones, vascular receptor expression, and related mechanisms, to elucidate the nuanced interactions between sympathetic activity, vascular function, and blood pressure regulation. Clarifying how these factors interact to influence autonomic regulation will be critical for developing targeted, sex-specific strategies to mitigate cardiovascular risk. A comprehensive synthesis of current findings, as summarized in Table 1 and Fig. 1, may guide future investigations aimed at improving cardiovascular health outcomes in females during the reproductive age. ACKNOWLEDGMENTS Figure 1 created with a licensed version of BioRender.com. DISCLOSURES No conflicts of interest, financial or otherwise, are declared by the authors. AUTHOR CONTRIBUTIONS J.S. and N.G.B. prepared figures; J.S., N.G.B., and J.K.L. drafted manuscript; J.S., N.G.B., and J.K.L. edited and revised manuscript; J.S., N.G.B., J.K.L., and C.W.U. approved final version of manuscript.

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Published by the American Physiological Society. History Received: 18 September 2025 Revision received: 9 October 2025 Accepted: 21 February 2026 Published ahead of print: 4 March 2026 Published in print: April 2026 Published online: 7 April 2026

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